Biological Activity of Oxidized Phospholipids

氧化磷脂的生物活性

• 批准号: 7162600
• 负责人: Thomas M McIntyre
• 金额: $ 32.64万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162600
• 关键词: Agonist; Apoptosis; Apoptotic; Arterial Fatty Streak; Atherosclerosis; Behavior; Binding; Biological; Blood Vessels; CCL2 gene; CD36 gene; Cells; Chronic; Condition; Disease; Elements; Event; Feedback; Figs - dietary; Foam Cells; Gene Expression; Genes; Genetic Transcription; Human; Indium; Inflammation; Inflammatory; Life; Ligands; Lipids; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Mediator of activation protein; Nature; Necrosis; Nuclear Hormone Receptors; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Phagocytes; Phagocytosis; Phosphatidylserines; Phospholipase; Phospholipids; Platelet Activating Factor; Process; Reaction; Relative (related person); Research Personnel; Role; Route; Signal Transduction; Surface; Testing; Yeasts; atherogenesis; behavior change; cytochrome c; cytokine; extracellular; gene induction; macrophage; monocyte; novel; oxidation; oxidized low density lipoprotein; platelet activating factor receptor; programs; receptor; response; scavenger receptor; transcription factor; uptake

DESCRIPTION (provided by applicant): The chronic inflammatory reaction of atherosclerosis remodels major vessels. LDL oxidation is an early event that may be causal, but certainly contributes to the disease process because it creates inflammatory mediators that attract monocytes, and activates vascular cells and these infiltrating monocytes. Monocytes store intracellular lipids following uptake of oxidized LDL, aided by the scavenger receptor CD36, to form foam cells. Oxidized LDL is atherogenic, and it is phospholipid oxidation that changes LDL behavior. Phospholipid oxidation products, we find, are biologically active because some engage and stimulate the receptor for the inflammatory phospholipid platelet-activating factor (PAF), while others potently bind and activate the nuclear hormone receptor and transcription factor PPARgamma. PPARgamma is present in atherosclerotic lesions where it controls expression of CD36 and foam cell formation. Conversely at higher concentrations oxidized LDL becomes toxic, with less being known about the molecules that cause apoptosis. The cytokine MCP-1 is essential for atherogenesis, and PAF-like lipids and PPAR gamma agonists induce its synthesis under different conditions. We now find that there is a third, currently undefined, route to the induction of the key, pro-atherogenic cytokine MCP-1. Oxidized phospholipids therefore act at several levels, from gene induction to apoptosis, in atherogenesis. We propose that: 1) the PPARy ligands that control the function of the transcription factor PPARgamma are present in atherosclerotic lesions. 2) undefined PPAR gamma-dependent and PPAR gamma-independent mechanisms induce MCP-1 synthesis following LDL oxidation. 3) oxidized phospholipids are early, common, and essential components of apoptosis 4) display of oxidized phosphatidylserine on the surface of apoptotic cells marks them for macrophage engulfment, which subsequently activates these phagocytes. 5) all these events are controlled by the oxidized phospholipid phospholipase PAF acetylhydrolase.

描述（由申请人提供）：动脉粥样硬化的慢性炎症反应重塑了主要血管。 LDL氧化是一个可能是因果关系的早期事件，但肯定会导致疾病过程，因为它会产生吸引单核细胞并激活血管细胞和这些浸润的单核细胞的炎症介质。单核细胞储存了在氧化的LDL摄取后的细胞内脂质，并在清道夫受体CD36的帮助下形成泡沫细胞。氧化的LDL具有动脉粥样硬化，是磷脂氧化改变了LDL行为。 我们发现，磷脂氧化产物具有生物活性，因为有些人会吸引并刺激炎性磷脂血小板激活因子（PAF）的受体，而其他人则有力地结合并激活核激素受体和转录因子ppargamma。 ppargamma存在于动脉粥样硬化病变中，其中控制CD36和泡沫细胞形成的表达。相反，在较高的浓度下，氧化的LDL变得有毒，对引起凋亡的分子知之甚少。 细胞因子MCP-1对于动脉粥样硬化至关重要，在不同条件下，PAF样脂质和PPARγ激动剂诱导其合成。现在，我们发现有第三个，目前未定义的途径是诱导钥匙，亲动物细胞因子MCP-1的途径。因此，氧化的磷脂在动脉粥样硬化中起作用，从基因诱导到凋亡。我们提出：1）控制转录因子ppargamma功能的PPARY配体存在于动脉粥样硬化病变中。 2）未定义的PPARγ依赖性和PPARγ独立的机制在LDL氧化后诱导MCP-1合成。 3）氧化的磷脂是凋亡的早期，常见和必需成分4）在凋亡细胞表面上显示氧化的磷脂酰丝氨酸，标记它们是否会吞噬巨噬细胞，随后激活这些吞噬细胞。 5）所有这些事件均由氧化的磷脂磷脂酶PAF乙酰水合酶控​​制。